LRBA Deficiency in a Patient With a Novel Homozygous Mutation Due to Chromosome 4 Segmental Uniparental Isodisomy
Soler-Palacín, Pere (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Garcia-Prat, Marina (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Martín-Nalda, Andrea (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Franco-Jarava, Clara (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Rivière, Jacques G.. (Jeffrey Modell Foundation Excellence Center)
Plaja Rustein, Alberto (Hospital Universitari Vall d'Hebron)
Bezdan, Daniela (Universitat Pompeu Fabra)
Bosio, Mattia (Universitat Pompeu Fabra)
Martínez Gallo, Mónica (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ossowski, Stephan (Institute of Medical Genetics and Applied Genomics, University of Tübingen)
Colobrán Oriol, Roger (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Date:	2018
Abstract:	LRBA deficiency was first described in 2012 as an autosomal recessive disorder caused by biallelic mutations in the LRBA gene (OMIM #614700). It was initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and recurrent infection. However, further reports expanded this phenotype (including patients without hypogammaglobulinemia) and described LRBA deficiency as a clinically variable syndrome with a wide spectrum of clinical manifestations. We present the case of a female patient who presented with type 1 diabetes, psoriasis, oral thrush, and enlarged liver and spleen at the age of 8 months. She later experienced recurrent bacterial and viral infections, including pneumococcal meningitis and Epstein Barr viremia. She underwent two consecutive stem cell transplants at the age of 8 and 9 years, and ultimately died. Samples from the patient and her parents were subjected to whole exome sequencing, which revealed a homozygous 1-bp insertion in exon 23 of the patient's LRBA gene, resulting in frameshift and premature stop codon. The patient's healthy mother was heterozygous for the mutation and her father tested wild-type. This finding suggested that either one copy of the paternal chromosome 4 bore a deletion including the LRBA locus, or the patient inherited two copies of the mutant maternal LRBA allele. The patient's sequencing data showed a 1-Mb loss of heterozygosity region in chromosome 4, including the LRBA gene. Comparative genomic hybridization array of the patient's and father's genomic DNA yielded normal findings, ruling out genomic copy number abnormalities. Here, we present the first case of LRBA deficiency due to a uniparental disomy (UPD). In contrast to classical Mendelian inheritance, UPD involves inheritance of 2 copies of a chromosomal region from only 1 parent. Specifically, our patient carried a small segmental isodisomy of maternal origin affecting 1 Mb of chromosome 4.
Grants:	Ministerio de Ciencia e Innovación PI11/01086 Ministerio de Economía, Industria y Competitividad PI14/00405 Instituto de Salud Carlos III PI17/00660
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Primary immunodeficiency ; LRBA deficiency ; Uniparental disomy ; Whole exome sequencing ; Comparative genomic hybridization array
Published in:	Frontiers in immunology, Vol. 9 (october 2018) , ISSN 1664-3224

DOI: 10.3389/fimmu.2018.02397
PMID: 30386343

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